CN108671262B - Embolic agent and preparation method and application thereof - Google Patents

Embolic agent and preparation method and application thereof Download PDF

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CN108671262B
CN108671262B CN201810738914.6A CN201810738914A CN108671262B CN 108671262 B CN108671262 B CN 108671262B CN 201810738914 A CN201810738914 A CN 201810738914A CN 108671262 B CN108671262 B CN 108671262B
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agent
mobile phase
embolic agent
embolic
acrylonitrile
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CN108671262A (en
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李皓
甘盛龙
陈龙斌
周国富
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South China Normal University
Shenzhen Guohua Optoelectronics Co Ltd
Academy of Shenzhen Guohua Optoelectronics
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South China Normal University
Shenzhen Guohua Optoelectronics Co Ltd
Academy of Shenzhen Guohua Optoelectronics
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
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Abstract

The invention discloses an embolic agent and a preparation method and application thereof, wherein the embolic agent is generated by a reactant raw material through a cross-linking reaction, the reactant raw material comprises a dispersed phase and a mobile phase, the dispersed phase comprises poly (acrylamide-co-acrylonitrile), a cross-linking agent, a condensing agent and a solvent, the cross-linking agent contains at least two carboxyl groups, and the mobile phase comprises an emulsifier and mineral oil. The preparation process is simple, the prepared embolism material can block the nutrition delivery and absorption of the tumor, can expand in the tumor area to realize the fixed-point release and imaging after being combined with the magnetic resonance imaging substance and the fluorescence imaging reagent, and has better application prospect in the aspect of treating the tumor.

Description

Embolic agent and preparation method and application thereof
Technical Field
The invention relates to the field of medicines, in particular to an embolic agent and a preparation method and application thereof.
Background
Smart materials or smart materials are a new material that can sense changes in the surrounding environment and take responsive countermeasures against the changes in the environment. The stimuli-responsive material belongs to a kind of intelligent material, and under the stimulation of environmental factors (including light, temperature, pH, ionic strength, electric field, magnetic field, specific molecules and the like), certain physical and chemical properties (including phase state, form, surface energy, reaction rate, permeability and the like) of the material change correspondingly. The hydrogel is a hydrophilic but water-insoluble high molecular polymer with a cross-linked three-dimensional network structure, has certain swelling/deswelling behaviors under certain conditions, and has outstanding performances of conveying, permeability, energy conversion, adsorption separation, good biocompatibility and the like. The combination of hydrogel and intelligent material, intelligent hydrogel, is widely used in the subject fields of agriculture, industry, medicine, bioengineering, etc. due to its unique characteristics.
Temperature sensitive stimuli-responsive materials have also been one of the major concerns for stimuli-responsive materials research for many years. Depending on the temperature-dissolution behavior of the polymer material, it can be divided into two main categories: low critical solution temperature materials (LCST) and high critical solution temperature materials (UCST). A low critical solution temperature material (LCST), such as poly (N-isopropylacrylamide) (PNIPAm), below the critical temperature, the molecular chains of the material are in an extended state, exhibiting dissolution; above the critical temperature, the molecular chain of the material is in a shrinkage state and is expressed as precipitation (insolubility), and the temperature-sensitive material of the type is mainly applied to the construction of drug carriers, tissue engineering, biological imaging preparations and the like. In contrast to the temperature response behavior of common Low Critical Solution Temperature (LCST) materials, high critical solution temperature (UCST) materials repel solvent molecules below a critical temperature and attract and affinity with solvent molecules above the critical temperature. The temperature responsiveness is derived from intramolecular hydrogen bonds and electrostatic interactions, and the response range is related to the proportion of groups interacting in the polymer molecule. When the temperature is higher than UCST, hydrogen bonds among polymer molecules are destroyed, and the solubility is increased; when the temperature is lower than UCST, polymer molecules form aggregates through hydrogen bonding. Poly (acrylamide-co-acrylonitrile) (P (AAm-co-AN)) random copolymer is a non-ionic UCST material that is hydrophobic (insoluble in water) at UCST temperatures and hydrophilic or completely water soluble above UCST temperatures, and such temperature sensitive materials are used as catalyst supports in patent CN104841483A published on 08/19/2015.
Malignant tumors are the most serious diseases threatening human health at present, and become the first cause of human death. The current diagnostic techniques for malignant tumors mainly include X-ray examination, angiography, CT detection, Magnetic Resonance Imaging (MRI), ultrasound angiography, and the like. The nuclear magnetic resonance imaging has the characteristics of nondestructive examination, wide imaging range, multi-aspect imaging, no bone radiography, high contrast and the like, and is an effective way for diagnosing malignant tumors. However, nuclear magnetic resonance imaging is not sensitive to calcification, calculus and cortical bone, so that the detection effect of the nuclear magnetic resonance imaging at certain parts is low, and diagnosis and differential diagnosis are not facilitated, so that the further improvement of the examination effect of the nuclear magnetic resonance imaging has positive significance for accurate diagnosis of tumors.
It is known that the cell metabolism of the tumor part is vigorous, higher than the normal tissue temperature, generally reaching more than 40 ℃ and locally exceeding 42 ℃. The application prospect of the temperature-sensitive material in tumor treatment is very wide, and how to apply the temperature-sensitive material to improve the effect of treating tumors becomes a problem to be solved in the field.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide an embolic agent, application and a preparation method thereof.
The technical scheme adopted by the invention is as follows:
the invention provides an embolic agent, which is generated by a cross-linking reaction of reactant raw materials comprising a dispersed phase and a mobile phase, wherein the dispersed phase comprises poly (acrylamide-co-acrylonitrile), a cross-linking agent, a condensing agent and a solvent, the cross-linking agent contains at least two carboxyl groups, and the mobile phase comprises an emulsifier and mineral oil.
Preferably, the crosslinking agent is a polyacid. Still further, the polybasic acid includes, but is not limited to, at least one of oxalic acid, trimesic acid, and triglycerides. In the application, trimesic acid is preferably adopted as a cross-linking agent, contains at least two carboxyl groups, is the smallest tricarboxy molecule in common molecules, can form a three-dimensional cross-linked network structure through the reaction of esterification and hydroxyl groups at two ends of poly (acrylamide-co-acrylonitrile), has small molecules, occupies small proportion in the whole structure, and can influence the whole temperature sensitivity as little as possible.
Preferably, the condensing agent is at least one of an esterification reaction condensing agent and an amidation reaction condensing agent. Still further, the condensing agent includes, but is not limited to, at least one of carbonyl diimidazole, a mixture of dicyclohexylcarbodiimide and 4-dimethylaminopyridine. In the present application, Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) can be used as a condensing agent in combination, so that the esterification reaction can be accelerated and the reaction efficiency can be improved. Similarly, Carbonyldiimidazole (CDI) and the like can also be used as an esterification condensing agent to improve the esterification efficiency.
Preferably, the poly (acrylamide-co-acrylonitrile): a crosslinking agent: the molar ratio of the condensing agent is 1: (1-10): (2-22).
Still further, the condensing agent is DCC and DMAP, the poly (acrylamide-co-acrylonitrile): a crosslinking agent: DCC: the molar ratio of DMAP was 1: (1-10): (2-20): (0.2-2).
Preferably, the poly (acrylamide-co-acrylonitrile): the mass ratio of the solvent is 5/95-10/90.
Preferably, the HLB value of the emulsifier is less than 10.
Further, the emulsifier is at least one of ABIL EM90, Span20, Span40 and Span 60.
Preferably, the mass fraction of the emulsifier in the mobile phase is 15wt% to 18 wt%.
Preferably, the embolic agent further comprises at least one of a magnetic resonance imaging substance, a fluorescent imaging agent. The magnetic resonance imaging substance and the fluorescence imaging reagent are loaded on the embolic agent and are used for realizing the site-specific release and imaging of the embolic agent.
Further, the magnetic resonance imaging substance is water-soluble paramagnetic nanoparticles. The water-soluble paramagnetic nanoparticles include, but are not limited to, Fe3O4、γ-Fe2O3、MeFe2O3At least one of (1).
Further, the fluorescent imaging reagent is at least one of fluorescent quantum dots, fluorescent protein and fluorescent molecules.
The invention also provides a preparation method of the embolic agent, which comprises the following steps:
(a) preparing a dispersed phase: dissolving poly (acrylamide-co-acrylonitrile) in a solvent to obtain a solution, and dissolving a cross-linking agent and a coupling agent in the solution to obtain a dispersed phase;
(b) preparing a mobile phase: dissolving an emulsifier in mineral oil to obtain a mobile phase;
(c) uniformly mixing the dispersed phase and the mobile phase to obtain gel;
(d) an optional step of adding at least one of a magnetic resonance imaging substance and a fluorescent imaging agent to the gel;
(e) and (c) carrying out heating reaction on the gel, and collecting the obtained embolic agent, wherein the sequence between the step (a) and the step (b) can be changed.
Preferably, the heating reaction in the step (e) is carried out at the temperature of 50-70 ℃ for 6-12 h.
Preferably, the dispersed phase and the mobile phase are mixed uniformly in step (c) by a microfluidic chip or a vortex shaker.
Preferably, the step (e) further comprises a step of washing with cyclohexane and ethanol after the heating reaction, specifically, adding the heated and reacted substances into an excessive cyclohexane solution, performing ultrasonic oscillation, performing centrifugal collection at 5000-7000 rpm, washing with absolute ethanol for 2-3 times, and collecting to obtain the embolic agent.
Preferably, the mass fraction of the poly (acrylamide-co-acrylonitrile) dissolved in the solvent in the step of preparing the dispersed phase in the step (a) is 5wt% to 10 wt%.
Preferably, the condensing agent in step (a) is a mixture of dicyclohexylcarbodiimide and 4-dimethylaminopyridine, and the crosslinking agent is trimesic acid.
Further, in step (a) the dispersed phase is poly (acrylamide-co-acrylonitrile): trimesic acid: dicyclohexylcarbodiimide: the molar ratio of the 4-dimethylamino pyridine is 1: (1-10): (2-20): (0.2-2).
Preferably, the flow speed of the dispersed phase is 0.4-1 muL/min when the micro-fluidic chip is added.
Preferably, the flow velocity of the mobile phase when the mobile phase is added into the microfluidic chip is 3.6-4 muL/min.
The use of the embolic agent in the preparation of a medicament for the treatment of a tumor.
The invention has the beneficial effects that:
the embolic agent provided by the invention adopts poly (acrylamide-co-acrylonitrile) (P (AAm-co-AN)) random copolymer of high critical solution temperature (UCST) material as raw material, so that the prepared embolic agent has temperature sensitivity, the UCST temperature of the embolic agent is close to the tumor core temperature, when the embolic agent reaches a high-temperature part, the embolic agent expands based on the temperature response characteristic of the material, the particle size is increased, the adaptive expansion positioning effect similar to thrombus can be realized, the nutrition delivery and absorption of tumor can be blocked, and the embolic agent can expand in a tumor area to realize fixed-point release and imaging after being combined with magnetic resonance imaging substances and fluorescence imaging reagents.
According to the invention, the emulsifier is added into the mineral oil, so that the P (AAm-co-AN) droplets emulsified and dispersed in the solvent can be stably dispersed in the mineral oil, and the micron-sized P (AAm-co-AN) three-dimensional cross-linked microgel spheres with controllable and uniform granularity can be guaranteed to be formed. The conventional embolic agent is made to be large in size, and can be injected at fixed points or locally to avoid blocking other blood vessels, the embolic agent prepared by the preparation method of the embolic agent provided by the invention is uniform in particle size, good in polydispersity, narrow in central particle size distribution, capable of being directly injected intravenously, spontaneously blocked at a tumor part through blood circulation, and capable of automatically identifying or targeting tumors.
Drawings
FIG. 1 is a microscope picture of the embolic agent prepared in example 1;
FIG. 2 is a graph of the temperature response of the embolic agent prepared in example 2;
FIG. 3 shows the superparamagnetic Fe supported Fe prepared in example 33O4An embolic agent of nanoparticles;
FIG. 4 is an embolic agent supporting fluorescent quantum dots prepared in example 4;
FIG. 5 is the temperature controlled release process of the embolic agent loaded with fluorescent quantum dots of example 5.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.
Example 1
Taking 2-mercaptoethanol, carbon disulfide and dibromo-p-xylene as raw materials, wherein the molar ratio of the raw materials to the raw materials is 2: 6: 1 in acetone to synthesize the thiocarbonate chain transfer agent with a symmetrical structure. Then, taking acrylamide and acrylonitrile as raw materials, and mixing the raw materials in a mass ratio of 55: 45 in DMF solution and adding a chain transfer agent (1/100 molar mass based on acrylonitrile content) to prepare a random copolymeric UCST polymeric material P (AAm-co-AN) by RAFT free radical polymerization.
Dissolving P (AAm-co-AN) with DMF organic solvent to prepare 5wt% organic solution, and according to the molar weight of the polymer P (AAm-co-AN), adding the following components in percentage by weight: trimesic acid: dicyclohexylcarbodiimide (DCC): 4-Dimethylaminopyridine (DMAP) in a 1: 7: 20: 2 weighing trimesic acid, Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) and dissolving in the organic solution to prepare a dispersed phase. Cetyl polyethylene glycol/polypropylene glycol-10/1 dimethicone (ABIL EM90) was dissolved in mineral oil at 15wt% by mass to form a mineral oil solution containing an emulsifier to obtain a mobile phase. And respectively connecting the dispersed phase and the mobile phase to a sample introduction channel of the microfluidic chip through an injector, wherein the flow rate of the dispersed phase is 0.7 mu L/min, and the flow rate of the mobile phase is 3.8 mu L/min, so as to generate and collect spherical microgel with uniform diameter. And then heating the collected spherical microgel for reaction for 12h at the reaction temperature of 60 ℃, adding the spherical microgel after the heating reaction into an excessive cyclohexane solution after the reaction is finished, carrying out ultrasonic oscillation, carrying out centrifugal collection at 5000rpm, and washing with absolute ethyl alcohol for 2 times to obtain the cross-linked embolic agent.
The prepared embolic agent is observed under a polarizing microscope in a bright field, a microscopic picture of the embolic agent is shown in figure 1, and the prepared embolic agent has uniform grain diameter and good polydispersity, the central grain diameter is mainly distributed in 5-8 μm, and the embolic agent can be well dispersed in ultrapure water.
Example 2
Dissolving P (AAm-co-AN) with DMF organic solvent to prepare 5wt% organic solution, and according to the molar weight of the polymer P (AAm-co-AN), adding the following components in percentage by weight: trimesic acid: dicyclohexylcarbodiimide (DCC): 4-Dimethylaminopyridine (DMAP) in a 1: 7: 20: 2 weighing trimesic acid, Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) and dissolving in the organic solution to prepare a dispersed phase. Cetyl polyethylene glycol/polypropylene glycol-10/1 dimethicone (ABIL EM90) was dissolved in mineral oil at 15wt% by mass to form a mineral oil solution containing an emulsifier to obtain a mobile phase. According to the dispersed phase: the mass ratio of the mobile phase is 1: 25, dropwise adding the dispersed phase into the mobile phase, performing high-speed vortex oscillation, and performing probe ultrasound on the emulsion subjected to the vortex oscillation by using an ultrasonic crusher to generate and collect spherical microgel with uniform diameter. And then heating the collected spherical microgel for reaction for 12h at the reaction temperature of 60 ℃, adding the spherical microgel after the heating reaction into an excessive cyclohexane solution after the reaction is finished, carrying out ultrasonic oscillation, carrying out centrifugal collection at 5000rpm, and washing with absolute ethyl alcohol for 2 times to obtain the cross-linked embolic agent.
Observing the temperature response characteristic of the prepared cross-linked embolic agent under a polarizing microscope in a bright field, wherein the obtained embolic agent shown in figure 2 absorbs water to swell when the temperature is increased, the surface optical property of the embolic agent is close to that of water phase, the surface optical property is transparent, and the particle size is reduced, such as that when the temperature is increased to 60 ℃ (10min), the particle size of the embolic agent is reduced to 9.2 μm, 17.9 μm and 19.3 μm, 11.1 μm and 12.8 μm; when the temperature returns to room temperature, the embolic agent dehydrates and returns to the original state again.
Example 3
Dissolving P (AAm-co-AN) with DMF organic solvent to prepare 5wt% organic solution, and measuring 1mg/mL polyethyleneimine modified Fe according to volume ratio of 5:13O4Uniformly mixing the nano-particle aqueous solution with a DMF (dimethyl formamide) solution of P (AAm-co-AN) to form a solution, wherein the molar weight of the polymer P (AAm-co-AN) is as follows: trimesic acid: dicyclohexylcarbodiimide (DCC): 4-Dimethylaminopyridine (DMAP) in a 1: 7: 20: 2 weighing trimesic acid, Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) and dissolving in the solution to prepare a dispersed phase. Cetyl polyethylene glycol/polypropylene glycol-10/1 dimethicone (ABIL EM90) was dissolved in mineral oil at 15wt% by mass to form a mineral oil solution containing an emulsifier to obtain a mobile phase. According to the dispersed phase: the mass ratio of the mobile phase is 1: 25, dropwise adding the dispersed phase into the mobile phase, performing high-speed vortex oscillation, and performing probe ultrasound on the emulsion subjected to the vortex oscillation by using an ultrasonic crusher to generate and collect spherical microgel with uniform diameter. Then heating the collected spherical microgel for 12h to react at 60 ℃, adding the spherical microgel after the heating reaction into excessive cyclohexane solution after the reaction is finished, carrying out ultrasonic oscillation, centrifugally collecting at 5000rpm, and washing with absolute ethyl alcohol for 2 times to obtain the Fe loaded with superparamagnetism3O4Cross-linked embolic agents of nanoparticles.
The prepared loaded superparamagnetic Fe is observed under the bright field of a polarizing microscope3O4The microscopic picture of the nanoparticle-crosslinked embolic agent is shown in fig. 3, from which it can be seen that the prepared superparamagnetic Fe-supported embolic agent is3O4The cross-linked embolic agent of the nanoparticles has uniform particle size and good polydispersity, and can be well dispersed in ultrapure water. Superparamagnetic Fe Supported in the present example3O4The cross-linked embolic agent of the nano particles can be used as a precise carrier system for site-specific release and is expected to be used for precise imaging of tumors, and on the other hand, due to the characteristics of the UCST material, the self-adaptive expansion positioning effect similar to that of thrombus can be realized, the nutrition delivery and absorption of the tumors are hindered, and a certain tumor treatment effect is achieved.
Example 4
Dissolving P (AAm-co-AN) with a DMF organic solvent to prepare AN organic solution with the concentration of 5wt%, measuring 8 mu mol/mL amino water-soluble quantum dots ZnCdSe/ZnS 10 mu L and a DMF solution of P (AAm-co-AN) to be uniformly mixed to form a solution, and according to the molar weight of the polymer P (AAm-co-AN), according to the molar weight of P (AAm-co-AN): trimesic acid: dicyclohexylcarbodiimide (DCC): 4-Dimethylaminopyridine (DMAP) in a 1: 7: 20: 2 weighing trimesic acid, Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) and dissolving in the solution to prepare a dispersed phase. Cetyl polyethylene glycol/polypropylene glycol-10/1 dimethicone (ABIL EM90) was dissolved in mineral oil at 15wt% by mass to form a mineral oil solution containing an emulsifier to obtain a mobile phase. According to the dispersed phase: the mass ratio of the mobile phase is 1: 25, dropwise adding the dispersed phase into the mobile phase, performing high-speed vortex oscillation, and performing probe ultrasound on the emulsion subjected to the vortex oscillation by using an ultrasonic crusher to generate and collect spherical microgel with uniform diameter. And then heating the collected spherical microgel for reaction for 12h at the reaction temperature of 60 ℃, adding the spherical microgel after the heating reaction into an excessive cyclohexane solution after the reaction is finished, carrying out ultrasonic oscillation, carrying out centrifugal collection at 5000rpm, and washing with absolute ethyl alcohol for 2 times to obtain the crosslinked embolic agent loaded with the amino water-soluble quantum dots.
The prepared amino-loaded water-soluble quantum dot-loaded cross-linked embolic agent is observed under a fluorescence microscope, and the result is shown in fig. 4, wherein the prepared embolic agent is a three-dimensional spherical structure.
Example 5
Dissolving P (AAm-co-AN) with a DMF organic solvent to prepare AN organic solution with the concentration of 5wt%, measuring 8 mu mol/mL amino water-soluble quantum dots ZnCdSe/ZnS 10 mu L and a DMF solution of P (AAm-co-AN) to be uniformly mixed to form a solution, and according to the molar weight of the polymer P (AAm-co-AN), according to the molar weight of P (AAm-co-AN): trimesic acid: dicyclohexylcarbodiimide (DCC): 4-Dimethylaminopyridine (DMAP) in a 1: 7: 20: 2 weighing trimesic acid, Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) and dissolving in the organic solution to prepare a dispersed phase. Cetyl polyethylene glycol/polypropylene glycol-10/1 dimethicone (ABIL EM90) was dissolved in mineral oil at 15wt% by mass to form a mineral oil solution containing an emulsifier to obtain a mobile phase. According to the dispersed phase: the mass ratio of the mobile phase is 1: 25, dropwise adding the dispersed phase into the mobile phase, performing high-speed vortex oscillation, and performing probe ultrasound on the emulsion subjected to the vortex oscillation by using an ultrasonic crusher to generate and collect spherical microgel with uniform diameter. And then heating the collected spherical microgel for reaction for 12h at the reaction temperature of 60 ℃, adding the spherical microgel after the heating reaction into an excessive cyclohexane solution after the reaction is finished, carrying out ultrasonic oscillation, carrying out centrifugal collection at 5000rpm, and washing with absolute ethyl alcohol for 2 times to obtain the crosslinked embolic agent loaded with the amino water-soluble quantum dots.
The characteristics of temperature-controlled release of the embolic agent are studied by heating the embolic agent to 60 ℃ using a microfluidic channel under a fluorescence microscope, and the results are shown in fig. 5, which shows that the fluorescence intensity of the embolic agent gradually decreases until the fluorescence disappears completely when the temperature increases. Namely, when the environmental temperature of the cross-linked embolic agent loaded with the amino water-soluble quantum dots rises, the microgel expands, and the loaded fluorescent quantum dots are released from the microgel.
Example 6
Preparing AN organic solution with the concentration of P (AAm-co-AN) of 10wt% by taking DMF as a solvent, wherein the molar amount of the polymer P (AAm-co-AN) is as follows: trimesic acid: dicyclohexylcarbodiimide (DCC): 4-Dimethylaminopyridine (DMAP) in a 1: 10: 2: 0.2 trimesic acid, Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) were weighed and dissolved in the above organic solution to prepare a dispersed phase. Cetyl polyethylene glycol/polypropylene glycol-10/1 dimethicone (ABIL EM90) was dissolved in mineral oil at 18wt% by mass to form a mineral oil solution containing an emulsifier to obtain a mobile phase. And respectively connecting the dispersed phase and the mobile phase to a sample introduction channel of the microfluidic chip through an injector, wherein the flow rate of the dispersed phase is 0.7 mu L/min, and the flow rate of the continuous phase is 3.8 mu L/min, so as to generate and collect spherical microgel with uniform diameter. And then heating the collected spherical microgel for 6h to react at 70 ℃, adding the spherical microgel after the heating reaction into excessive cyclohexane solution after the reaction is finished, carrying out ultrasonic oscillation, carrying out centrifugal collection at 5000rpm, and washing with absolute ethyl alcohol for 2 times to obtain the cross-linked embolic agent.
Example 7
Preparing AN organic solution with the concentration of P (AAm-co-AN) of 5wt% by taking DMF as a solvent, wherein the molar amount of the polymer P (AAm-co-AN) is as follows: trimesic acid: dicyclohexylcarbodiimide (DCC): 4-Dimethylaminopyridine (DMAP) in a 1: 1: 20: 2 weighing trimesic acid, Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) and dissolving in the organic solution to prepare a dispersed phase. Cetyl polyethylene glycol/polypropylene glycol-10/1 dimethicone (ABIL EM90) was dissolved in mineral oil at 18wt% by mass to form a mineral oil solution containing an emulsifier to obtain a mobile phase. And respectively connecting the dispersed phase and the mobile phase to a sample introduction channel of the microfluidic chip through an injector, wherein the flow rate of the dispersed phase is 0.7 mu L/min, and the flow rate of the continuous phase is 3.8 mu L/min, so as to generate and collect spherical microgel with uniform diameter. And then heating the collected spherical microgel for reaction for 12h at 50 ℃, after the reaction is finished, adding the spherical microgel after the heating reaction into an excessive cyclohexane solution, carrying out ultrasonic oscillation, centrifugally collecting at 7000rpm, and washing for 3 times by using absolute ethyl alcohol to obtain the cross-linked embolic agent.
Example 8
Preparing AN organic solution with the concentration of P (AAm-co-AN) of 8wt% by taking DMF as a solvent, wherein the molar amount of the polymer P (AAm-co-AN) is as follows: trimesic acid: carbonyldiimidazole (CDI) molar ratio of 1: 1: and 15, weighing trimesic acid and Carbonyl Diimidazole (CDI) to be dissolved in the organic solution to prepare a dispersed phase. Cetyl polyethylene glycol/polypropylene glycol-10/1 dimethicone (ABIL EM90) was dissolved in mineral oil at 18wt% by mass to form a mineral oil solution containing an emulsifier to obtain a mobile phase. And respectively connecting the dispersed phase and the mobile phase to a sample introduction channel of the microfluidic chip through an injector, wherein the flow rate of the dispersed phase is 1 mu L/min, and the flow rate of the continuous phase is 4 mu L/min, so as to generate and collect spherical microgel with uniform diameter. And then heating the collected spherical microgel for reaction for 12h at 50 ℃, after the reaction is finished, adding the spherical microgel after the heating reaction into an excessive cyclohexane solution, carrying out ultrasonic oscillation, centrifugally collecting at 7000rpm, and flushing for 3 times by using absolute ethyl alcohol to obtain the cross-linked embolic agent.

Claims (10)

1. The preparation method of the embolic agent is characterized by comprising the following steps:
(a) preparing a dispersed phase: dissolving poly (acrylamide-co-acrylonitrile) in a solvent to obtain a solution, wherein the mass fraction of the poly (acrylamide-co-acrylonitrile) in the solution is 5-10 wt%, and dissolving a cross-linking agent and a condensing agent in the solution to obtain a dispersed phase, wherein the cross-linking agent contains at least two carboxyl groups;
(b) preparing a mobile phase: dissolving an emulsifier in mineral oil to obtain a mobile phase;
(c) uniformly mixing a dispersion phase and a mobile phase to obtain gel, wherein the flow rate of the dispersion phase is 0.4-1 mu L/min and the flow rate of the mobile phase is 3.6-4 mu L/min during mixing;
(d) an optional step of adding at least one of a magnetic resonance imaging substance and a fluorescent imaging agent to the gel;
(e) heating the gel for reaction, and collecting the embolic agent, wherein the sequence between the step (a) and the step (b) can be changed;
wherein the crosslinking agent is trimesic acid.
2. The method for preparing an embolic agent according to claim 1, wherein the heating reaction in step (e) is performed at 50 to 70 ℃ for 6 to 12 hours.
3. The method of claim 1, wherein the condensing agent is an esterification condensing agent.
4. The method of claim 1, wherein the poly (acrylamide-co-acrylonitrile): a crosslinking agent: the molar ratio of the condensing agent is 1: (1-10): (2-22).
5. The method of claim 1, wherein the poly (acrylamide-co-acrylonitrile): the mass ratio of the solvent is 5/95-10/90.
6. The method of claim 1, wherein the emulsifier has an HLB value of less than 10.
7. The method for preparing the embolic agent according to claim 1, wherein the mass fraction of the emulsifier in the mobile phase is 15wt% to 18 wt%.
8. The method of claim 1, wherein the magnetic resonance imaging material is water-soluble paramagnetic nanoparticles.
9. The method for preparing the embolic agent according to claim 1, wherein the fluorescent imaging agent is at least one of a fluorescent quantum dot, a fluorescent protein, and a fluorescent molecule.
10. Use of an embolic agent prepared according to the method of manufacture of any of claims 1-9 for the manufacture of a medicament for the treatment of a tumor.
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